Erythropoietin is sold under the labels PROCRIT (epoetin), EPOGEN (epoetin), and ARANESP (darbepoetin). Erythropoietin is indicated for treatment of anemia, particularly anemia associated with chronic renal failure and cancer chemotherapy. Erythropoietin (Epo), an angiogenic factor, increases hematocrit and hemoglobin concentrations via the stimulation of erythropoiesis, resulting in increased blood viscosity (1-5) and blood pressure (1-14). In clinical studies, approximately one-third of hemodialysis patients treated with recombinant human Epo have shown an increase in blood pressure. Epo has been postulated to increase peripheral vascular resistance and decrease cardiac output due to increased viscosity (6). Others have suggested additional mechanisms for Epo-caused hypertension, such as hypervolemia, increased plasma renin and angiotensin, along with adrenergic over activity, increased plasma arginine vasopressin, decreased kinins and prostaglandins (15). An excessive, lasting elevation of circadian amplitude, blood pressure over-swinging and an elevation of blood pressure may be based on vasomotor chronome (time structure) alteration. Hormones and other agents, in part on a genetic basis, may be contributing factors to the circadian blood pressure variation. Hypertension is one of the most important risk factors in the development of cardiovascular complications. Hypertension is affected significantly by circadian rhythms. Hormonal concentration in the body fluctuates during the day and night with prominent spontaneous circadian (about-24-hour) changes that affect blood pressure and heart rate. There are also sufficiently important rhythms that can make the difference between the stimulation versus the inhibition of a malignancy. Epo is a 34 kDa glycoprotein hormone that is produced by the interstitial cells in the peritubular capillary bed of the mammalian kidney and the perivenenous hepatocytes of the liver (3). Epo is secreted in response to hypoxia to coordinate erythropoiesis as a primary inducer and regulator of red-cell differentiation by suppressing apoptosis and triggering cell division and terminal maturation of blood cell progenitors (16). These effects are mediated through the binding of Epo to specific cell surface receptors (17). The primary structure of human Epo has been known since the mid-1980s (18,19), but the structural features of the Epo molecule that confer its biological activity are largely unknown. Human Epo contains two disulfide bonds that link cysteine 29 with cysteine 33, and cysteine 7 with cysteine 161. Both bonds are essential for biological activity (18). Epoetin (recombinant human erythropoietin) was produced following isolation of the human gene and its expression in a Chinese hamster's ovarian cell line (4).
The recombinant Epo is a 165-amino acid mature protein that differs from the mature native protein only in lacking the carboxyl terminus arginine of the native protein. Native human Epo is translated as a 193-amino acid peptide, from which a 27-amino-acid leader sequence is cleaved off (19,20). Recombinant Epo has an apparent molecular weight of about 30.4 kDa, appears to be immunologically equivalent to the endogenous hormone, and exhibits full biological activity (19).
Epo-treated humans and animals exhibit increased hematocrit % and increased hemoglobin via the stimulation of erythropoiesis (2-5). Some study results suggest that increased hematocrit levels are correlated with an increased blood pressure in humans (20). Other studies involving the treatment of anemia with Epo showed increased hematocrit concentrations and resulting elevated blood severe enough to require treatment with antihypertensive medication pressure in 20-30% of patients (5). Hypertension is the most frequent and most important complication from treatment with erythropoietin. Furthermore, although the goal of Epo treatment is to increase hematocrit and hemoglobin, it has been found that the greater the increase of hematocrit, the greater the risk of mortality and cardiovascular events, see for example the “Procrit” website at “Procrit dot com” on the world wide web (PROCRIT warnings,). This may be due to blood pressure rise, since the extent of blood pressure rise has been shown to correlate with the extent of hematocrit increase (20). The epoetin label warns that patients with uncontrolled hypertension should not be treated with epoetin.